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Introduction

Acute generalized exanthematous pustulosis (AGEP) is characterized by the abrupt onset of a widespread pustular erythematous skin rash often accompanied by systemic symptoms like fever or leucocytosis. It is drug induced in 90% of the cases (1,2) and occasionally related to hypersensitivity to mercury (3,4) or to a viral infection such as enterovirus, Epstein-Barr virus (EBV), cyto-megalovirus (CMV) and hepatitis B virus (1). It was rarely described in association with parvovirus B19 (B19V) infection (5).

Case report

We report the case of a 22-year-old male patient who was referred to our Dermatology Department for a rapid onset of pruriginous exanthema consisting of numerous small nonfollicular pustules arising on large areas of confluent maculopapular rash on the trunk and limbs (Figure 1). Concomitantly, he developed a symmetric well-demar-cated purpuric rash on his feet, resembling the feet lesions of the gloves and socks syndrome (Figure 2), but differed from the classical presentation of this syndrome, as no

similar lesions were observed on his hands or wrists. No fever was registered. He suffered from congenital car-diopathy and atrial fibrillation and was medicated with lisinopril, bisoprolol, furosemide and warfarin for many years. No history of psoriasis or contact with mercury was mentioned. He started oral amoxicillin/clavulanic acid 7 days before for a dental infection and received oral allopurinol 12 h before for hyperuricemia. The complete blood count was remarkable for neutrophilia (9610/mm3) while the serum chemistries were within the normal range and the serologic markers for human immunode-ficiency virus, hepatitis B e C viruses were negative. The skin biopsy showed a subcorneal pustule and perivascu-lar inflammatory infiltrate with the participation of neu-trophils and eosinophils, consistent with AGEP (Figure 3). The polymerase chain reaction (PCR) test was strongly positive for B19V in the skin fragment and negative for CMV, EBV and human herpesvirus 6 (HHV6) in the blood sample. The serology detected by enzyme-linked immu-noassay (ELISA) showed negative antiparvovirus-B19-IgM antibodies and positive IgG antibodies with a titer of 2.3 RU/mL. Amoxicillin/clavulanic acid and allopurinol were suspended and oral prednisolone at 0.8 mg/kg was

Case RepoRt

Acute generalized exanthematous pustulosis to amoxicillin associated with parvovirus B19 reactivation

Ana Maria Calistru1, Carmen Lisboa1,2, Ana Paula Cunha1,2, Herberto Bettencourt3, and Filomena Azevedo1

1Hospital São João EPE, Dermatology and Venereology, Alameda Prof. Hernani Monteiro, Porto, Portugal, 2Faculty of Medicine (U38/FCT), University of Porto, Porto, Portugal, and 3Hospital São João EPE, Pathology, Porto, Portugal

abstractWe report the case of a 22-year-old male patient with 2 episodes, 4 months apart, of acute generalized exanthematous pustulosis (AGEP) associated with oral intake of amoxicillin and simultaneous reactivation of parvovirus B19 infection proven by positive polymerase chain reaction test in the skin fragment and blood sample and elevation of the IgG antibodies titer. To our knowledge, this is the first report of AGEP resulting from the interaction between drug hypersensitivity and the reactivation of parvovirus B19. A combination of an immunological reaction to the drug and virus infection could be responsible for the clinical picture.Keywords: Drug reaction, cutaneous, virus infection

Address for Correspondence: Ana Maria Calistru, Hospital São João EPE, Dermatology and Venereology, Alameda Prof. Hernani Monteiro, Porto, 4200-319 Portugal. E-mail: anagruia@yahoo.com

(Received 05 October 2011; revised 07 November 2011; accepted 26 November 2011)

Cutaneous and Ocular Toxicology, 2012; 31(3): 258–261© 2012 Informa Healthcare USA, Inc.ISSN 1556-9527 print/ISSN 1556-9535 onlineDOI: 10.3109/15569527.2011.645978

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started with rapid resolution of the rash. The IgG serology for parvovirus-B19 repeated after 2 months was posi-tive, with a decreased titer (1.8 RU/mL). The patch tests performed with amoxicillin, amoxicillin/clavulanic acid and allopurinol 1%, 5%, 10% and 20% in petrolatum were negative. Despite being advised to avoid the two drugs, the patient took oral amoxicillin for a respiratory tract infection 4 months later. At this time, generalized pustular eruption appeared again after 9 days, with rapid resolu-tion in a few days. No purpuric lesions were registered

this time. The PCR test in the blood sample was positive for B19V (<500 copies/mL) and negative for CMV, EBV and HHV6. The antiparvovirus-B19-IgM antibodies were negative while IgG showed a high titer (>200 RU/mL). The patient avoided amoxicillin intake and no skin eruption was mentioned during 4 months of follow-up; the PCR test for B19V continued positive in the blood sample (<500 copies/mL), and the IgG titer was 99 RU/mL (Figure 4).

Discussion

AGEP diagnosis was established in our patient due to the sudden onset of typical generalized nonfollicular pustu-lar rash associated to neutrophilia and consistent histo-logical findings. Despite negative patch tests, reported to have a sensitivity of 50%–80% in AGEP (6), the relation of causality with amoxicillin was stated based on the reappearance of the pustular rash after the reexposure to amoxicillin. We excluded clavulanic acid and allopurinol as potential causative agents because the second episode was associated with amoxicillin alone.

Human parvovirus B19 belongs to the genus Erythrovirus of the family of Parvoviridae and produc-tively replicates in the erythroid progenitor cells. Its sero-prevalence is of more than 70% in the adult population (7). The dermatologic manifestations of the B19V infec-tion are erythema infectiosum (fifth disease) in children and purpuric eruptions on the hands and feet (“gloves and socks” syndrome) in adults. Rarely, other cutaneous manifestations have been reported to be associated with B19V including vasculitis, erythema nodosum, the lupus eythematosus-like syndrome, pityriasis lichenoides (8), vesiculopustular eruption (9) and AGEP (5). After the pri-mary infection, the IgG antibodies are present throughout the life. Persisting infection may be observed in immu-nocompromised patients unable to produce neutralizing antibodies (10) and they can develop symptomatic B19 infections as a result of reactivation of latent or persistent viral infection (11).

Figure 1. Generalized exanthema consisting of numerous small nonfollicular pustules arising on large areas of confluent maculopapular rash.

Figure 2. Well-demarcated purpuric rash on the feet.

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260 A. M. Calistru et al.

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Recently, persisting low levels of B19V DNA have been evidenced in the blood of the immunocompetent individuals several years after the primary infection, the mechanism of such chronic carriage being unclear (10). Our patient had no immunosuppressive factor and dem-onstrated the persistence of B19V in the blood with levels of <500 copies/mL on two occasions 4 months apart. The strongly positive PCR test in the lesional skin demon-strates the involvement of the B19V infection, most prob-ably by reactivation, as the IgM antibodies were negative. As seen in Figure 4, the IgG antibodies recorded two peaks, at the time of each episode of pustular eruption, corresponding to virus reactivation.

A Th1-mediated immune response is mounted both in AGEP (1) and in B19V infection (12), so a common path-way in their pathophysiology may be found.

Sidoroff et al. identified two different temporal patterns of AGEP reaction from the beginning of drug administra-tion to the onset of skin lesions: for antibiotic exposure the median interval was 1 day, while for all other drugs the median interval was 11 days (13). The longer than expected interval between the amoxicillin intake and AGEP manifestation in our patient may be explained by the time delay to virus reactivation.

The interaction between virus infection and cutane-ous drug eruption has been described in the literature, for example the morbiliform eruption of patients with

infectious mononucleosis taking aminopenicillins or the association between drug rash with eosinophilia and systemic symptoms (DRESS) and HHV6 reactivation. It has been proposed that in susceptible people, a tran-sient drug-induced hypogammaglobulinemia creates an immunological environment that allows viral reactiva-tion (14). Some studies suggest that not only HHV6 but also other herpesvirus might reactivate from the latency and play an important role in the appearance of clinical manifestations of DRESS (15).

To our knowledge, this is the first report of AGEP man-ifestation resulting from the interaction between drug hypersensitivity and the reactivation of parvovirus B19. A combination of immunological reaction to the drug and B19V reactivation could be responsible for the clinical picture.

New insight in the biology of the parvovirus B19 and its interaction with the immune system may explain the interplay between drug reaction and virus reactivation.

Declaration of interest

The authors report no declarations of interest.

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Figure 3. Subcorneal pustule and perivascular inflammatory infiltrate with the participation of neutrophils and eosinophils.

Figure 4. The dynamics of the parvovirus B19 IgG serology (on logarithmic scale).

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